In these mice, only the ubiquitous antigen-specific TR1 cells suppressed liver autoimmunity. Thus, the scope of antigen spreading in autoimmune disorders is larger than previously anticipated, involving specificities expected to be silenced by mechanisms of tolerance; the regulatory activity, but not the retention of autoreactive TR1 cells, requires local autoantigen expression.Tregs require specific epigenetic signatures to induce and maintain their suppressive function in the context of inflammation and cancer surveillance. In this issue of the JCI, Xiong and colleagues identify a critical role for the epigenetic repressor REST corepressor 1 (CoREST) in promoting Treg suppressive transcriptional and functional programs. Pharmacologic inhibition and genetic loss of CoREST in Tregs impaired organ allograft tolerance and unleashed antitumor immunity via epigenetic activation of effector T cell programs. We propose that exploiting epigenetic control mechanisms will further the translation of Treg-based therapeutics to target inflammatory and malignant disorders.Parathyroid hormone (PTH) has complex effects on bone, including stimulating bone formation and regulating the hematopoietic stem cell (HSC) niche. In the current issue of the JCI, Li et al. demonstrated that the microbiome, through the production of short-chain fatty acids and in particular, butyrate, is necessary for the ability of PTH to increase osteoblast numbers and stimulate bone formation. In addition to implications for the treatment of osteoporosis with PTH analogs, this pathway may be part of a broader mechanism through which the microbiome serves its key function of modulating the immune system.Detailed spatial information of low-molecular-weight compounds distribution, especially in the brain, is crucial towards understanding their mechanism of actions. Imaging techniques that can directly visualize drugs in the brain at a high resolution will complement existing tools for drug distribution analysis. https://www.selleckchem.com/products/Romidepsin-FK228.html Here, we performed surface-enhanced Raman scattering (SERS) imaging using a bioorthogonal alkyne tag to visualize drugs directly in situ at a high resolution. Focusing on the selective serotonin reuptake inhibitor S-citalopram (S-Cit), which possesses a nitrile group, we substituted an alkynyl group into its structure and synthesized alkynylated S-Cit (Alk-S-Cit). The brain transitivity and the serotonin reuptake inhibition of Alk-S-Cit were not significantly different as compared to S-Cit. Alk-S-Cit was visualized in the coronal mouse brain section using SERS imaging with silver nanoparticles. Further, SERS imaging combined with fluorescence microscopy allowed Alk-S-Cit to be visualized in the adjacent neuronal membranes, and in the brain vessel and parenchyma. Thus, our multimodal imaging technique is an effective method for detecting low-molecular-weight compounds in their original tissue environment and can potentially offer additional information regarding the precise spatial distribution of such drugs.Immune checkpoint inhibitor (ICI) therapy has shown a significant benefit in the treatment of a variety of cancer entities. However, immune-related adverse events (irAEs) occur frequently and can lead to ICI treatment termination. MicroRNA-146a (miR-146a) has regulatory functions in immune cells. We observed that mice lacking miR-146a developed significantly more severe irAEs compared to wildtype mice in several irAE target organs in two different murine models. MiR-146a-/- mice exhibited increased T cell activation and effector function upon ICI treatment. Moreover, neutrophil numbers in the spleen and the inflamed intestine were highly increased in ICI-treated miR-146a-/- mice. Therapeutic administration of a miR-146a mimic reduced irAE severity. To validate our preclinical findings in patients, we analyzed the impact of a SNP in the MIR146A gene on irAE severity in 167 patients treated with ICIs. We found that the SNP rs2910164 leading to reduced miR-146a expression was associated with an increased risk to develop severe irAEs, reduced progression-free survival and increased neutrophil counts both at baseline and during ICI therapy.In conclusion, we characterized miR-146a as a novel molecular target to prevent ICI mediated autoimmune dysregulation. Furthermore, we identified the MIR146A SNP rs2910164 as a biomarker to predict severe irAE development in ICI-treated patients.The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low tissue-resident CD8+ and CD4+ T-cell density (TRM) are unknown. We analyzed shedding episodes during chronic HSV-2 infection viral clearance always predominated within 24 hours of detection even if viral load exceeded 107 HSV DNA copies; surges in granzyme B and interferon-γ occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of TRM in situ proliferation, trafficking, cytolytic effects and cytokine alarm signaling from murine studies with viral kinetics, histopathology and lesion size data from humans. A sufficiently high density of HSV-2 specific TRM predicted rapid elimination of infected cells, but our data suggest that such TRM densities are relatively uncommon in infected tissues. At lower, more commonly observed TRM densities, TRM must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in order to eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.As there is growing evidence for the tumor microenvironment's (TME) role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was undetectable in breast cancer cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression.